Immune Responses in Neuronal Cell Death

视网膜神经节细胞（RGC）是唯一将视觉信号从眼睛传递到大脑的输出神经元。 RGC死亡是许多导致失明的视网膜疾病发病机制中的关键因素，例如 青光眼和视神经损伤。这些疾病也是退伍军人失明的主要原因。的 致盲性疾病在退伍军人中的患病率非常高，约20.5-63.4%的退伍军人被诊断为 至少一种眼部疾病。外伤性视神经病变是VA患者视力缺陷的重要原因 (TON)与创伤性脑损伤（TBI）有关。TBI是全球死亡和残疾的重要原因， 据估计，美国每年发生160 - 380万例新的TBI病例。大约57-66%的TBI退伍军人 视力问题和没有治疗TON比观察更有效。因此，视力的治疗 与TBI相关的损伤是VA医疗保健系统面临的重大挑战， 对这些疾病中介导RGC死亡的分子机制的认识不完全。在 除原发伤外，继发伤使损伤急剧恶化，约占TBI的40 死亡TBI和TON的重要继发性损伤之一是谷氨酸兴奋性毒性，其病理学改变是谷氨酸兴奋性毒性。 谷氨酸受体的过度刺激导致神经元受损并最终死亡的过程。 这一过程在其他神经退行性疾病中也起着关键作用，如青光眼， 损伤RGC。因此，有效地减少或防止谷氨酸兴奋毒性对于减少RGC至关重要 死亡和保存视力。基于对控制脆弱性的机制的理解， RGC，我们计划开发新的治疗策略，以防止这些疾病中的RGC死亡。 最近的研究表明，免疫分子在神经元修复和细胞死亡中起重要作用， 中枢神经系统疾病在视网膜中，主要组织相容性复合体（MHC）I类分子、T细胞受体和免疫球蛋白受体的表达与视网膜中的免疫球蛋白受体的表达密切相关。 受体（TCR）及其相关蛋白由RGC表达。这些分子的突变减少了 RGCs对谷氨酸兴奋性毒性和视神经挤压（ONC）的敏感性。这些发现强烈 支持MHCI/TCR可以保护RGC免于死亡的可能性。此外，RGC对 谷氨酸兴奋毒性和ONC在不同类型的RGC和病理类型之间存在显著差异。 侮辱。这些结果表明，多种机制调节RGCs的死亡，因此， 因此，需要相应地设计预防RGC在疾病中死亡的治疗策略。 在这项研究中，我们计划进行原理验证研究，以确定MHCI-TCR作为关键的免疫调节因子的作用。 谷氨酸兴奋毒性和ONC诱导的神经元损伤的介质。我们的初步结果显示， RGC对NMDA兴奋毒性和ONC的敏感性具有RGC类型依赖性，CD 3 z突变显著 降低RGC的易感性，Src家族成员Hck和ZAP 70的药理学抑制保护 RGC和RGC表达Hck和ZAP 70两者。我们将进一步确定Hck是否通过以下方式保护RGC： CD 3 z活化，Hck和ZAP 70抑制剂对RGCs的保护功效是否具有类型特异性，以及 抑制剂的全身应用是否与眼内注射一样有效地保护RGC（目的1）。我们 还将确定Hck和ZAP 70抑制剂对ONC中RGC的保护作用是否为RGC 依赖类型（目标2）。最后，我们将证明是否同时应用Hck或 ZAP 70与mGluR 1拮抗剂协同保护RGC并建立RGC的最佳策略 保护（目标3）。这项研究将使用最先进的药理学，遗传学，细胞学，成像， 电生理和行为方法，它有几个独特的优势：它是在一个强大的接地 然而，完全新颖的机制框架建立在当前的神经科学，它的目标是多眼损伤， VA患者中常见的疾病，并可能导致与几只眼睛相关的新治疗策略 退伍军人的疾病和TBI。

Retinal ganglion cells (RGCs) are the only output neurons that relay visual signals from the eyes to the brain. RGC death is a crucial element in the pathogenesis in many retinal diseases leading to blindness, such as glaucoma and optic nerve injury. These diseases are also the leading causes of blindness of veterans. The prevalence of blinding diseases in veterans is very high and about 20.5-63.4% of veterans were diagnosed with at least one ocular disease. A significant cause of vision defects of VA patients is traumatic optic neuropathy (TON) related to traumatic brain injury (TBI). TBI is a significant cause of death and disability worldwide, and it is estimated 1.6-3.8 million new TBI cases occur in the US each year. About 57-66% veterans with TBI had vision problems and no treatment for TON is more effective than observation. Therefore, the treatment of vision impairment related to TBI is a significant challenge for the VA healthcare system, and it has been limited by incomplete understanding of the molecular mechanisms that mediating the RGC death in these diseases. In addition to the primary injury, secondary injuries dramatically worsen the damage and cause about 40% of TBI deaths. One of the significant secondary injuries of TBI and TON is glutamate excitotoxicity, the pathological process by which neurons are damaged and eventually killed by excessive stimulation of glutamate receptors. This process also plays critical roles in other neurodegenerative diseases, such as glaucoma, which specifically injure RGCs. Therefore, effectively minimizing or preventing glutamate excitotoxicity is crucial to reduce RGCs death and preserve vision. Based on the understanding of the mechanisms which control the vulnerability of RGCs, we plan to develop novel treatment strategies to prevent RGC death in these diseases. Recent studies have shown that immune molecules play essential roles in neuron repair and cell death in CNS diseases. In the retina, the receptors of major histocompatibility complex (MHC) class I molecules, T-cell receptor, (TCR) and their associated proteins are expressed by RGCs. The mutation of these molecules reduced the susceptibility of RGCs to glutamate excitotoxicity and optic nerve crush (ONC). These findings strongly support the possibility that MHCI/TCR could protect RGCs from death. Also, the susceptibility of RGCs to glutamate excitotoxicity and ONC vary significantly among different types of RGC and the types of pathological insults. These results demonstrate that multiple mechanisms regulate the death of RGCs and, therefore, the treatment strategies to prevent RGC death in diseases need to be designed accordingly. In this study, we plan to conduct proof-of-principle studies to establish the role of MHCI-TCR as a critical mediator of neuronal injury induced by glutamate excitotoxicity and ONC. Our preliminary results showed that susceptibility of RGCs to NMDA excitotoxicity and ONC is RGC type-dependent, mutation of CD3z significantly reduces the susceptibility of RGCs, pharmacological inhibition of Src family member, Hck, and ZAP70 protects RGCs, and RGCs express both Hck and ZAP70. We will further determine whether Hck protects RGCs through CD3z activation, whether the protective efficacy of Hck and ZAP70 inhibitors on RGCs is type specific, and whether systemic application of the inhibitors protects RGCs as effective as an intraocular injection (Aim 1). We will also determine whether the protective efficacy of the inhibitors of Hck and ZAP70 on RGCs in ONC is RGC type-dependent (Aim 2). Finally, we will prove the principle of whether the co-application of inhibitors of Hck or ZAP70 with a mGluR1 antagonist protects RGCs synergistically and to establish the optimal strategy for RGC protection (Aim 3). The research will use state-of-art pharmacological, genetic, cellular, imaging, electrophysiological and behavioral approaches, which has several unique advantages: it is grounded in a robust yet entirely novel mechanistic framework built on current neuroscience, it targets multiple ocular injuries and diseases commonly seen in VA patients, and may lead to a novel therapeutic strategy relevant to several eye diseases and TBI in veterans.